2-241735134-C-G

Position:

• chr2-241735134-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152783.5(D2HGDH):​c.-91C>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,339,036 control chromosomes in the GnomAD database, including 1,472 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (210 hom., cov: 34)
  • Exomes 𝑓: 0.045 (1262 hom.)
• Consequence: D2HGDH NM_152783.5 splice_region
• Scores: Splicing: ADA: 0.00004807
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.54

Genes affected

D2HGDH (HGNC:28358): (D-2-hydroxyglutarate dehydrogenase) This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

ENSG00000215692 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-241735134-C-G is Benign according to our data. Variant chr2-241735134-C-G is described in ClinVar as [Benign]. Clinvar id is 335309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5	c.-91C>G		splice_region_variant	2/10	ENST00000321264.9	NP_689996.4
D2HGDH	NM_152783.5	c.-91C>G		5_prime_UTR_variant	2/10	ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9	c.-91C>G		splice_region_variant	2/10	1	NM_152783.5	ENSP00000315351.4
D2HGDH	ENST00000321264	c.-91C>G		5_prime_UTR_variant	2/10	1	NM_152783.5	ENSP00000315351.4

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6992 AN: 152230 Hom.: 208 Cov.: 34

Gnomad AFR AF: 0.0692

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0492

GnomAD4 exome AF: 0.0447 AC: 53068 AN: 1186694 Hom.: 1262 Cov.: 19 AF XY: 0.0436 AC XY: 25274 AN XY: 579824

Gnomad4 AFR exome AF: 0.0704

Gnomad4 AMR exome AF: 0.0315

Gnomad4 ASJ exome AF: 0.0273

Gnomad4 EAS exome AF: 0.0000669

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.0197

Gnomad4 NFE exome AF: 0.0490

Gnomad4 OTH exome AF: 0.0417

GnomAD4 genome AF: 0.0460 AC: 7001 AN: 152342 Hom.: 210 Cov.: 34 AF XY: 0.0428 AC XY: 3190 AN XY: 74500

Gnomad4 AFR AF: 0.0693

Gnomad4 AMR AF: 0.0375

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00993

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.0450

Gnomad4 OTH AF: 0.0487

Alfa AF: 0.0416 Hom.: 25

Bravo AF: 0.0499

Asia WGS AF: 0.0110 AC: 39 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

D-2-hydroxyglutaric aciduria 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.5
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62191976; hg19: chr2-242674549;